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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

(9). However, there is increasing evidence that this is not an isolated
phenomenon and that ATP released from the epithelial lining of
other organs such as the ureter, gut or bile duct following distension
may act on P2X3 receptors on afferent nerves in the subepithelial
plexuses to provide sensory feedback and, in the case of the ureter,
renal colic pain (see section on Pain). P2X3 receptors have been
found on the suburothelial nerve plexus and both the human and
guinea-pig ureter have been shown to release ATP in a pressure-
dependent fashion when distended. This ATP release is abolished
when the urothelium is removed, and sensory nerve-recording
studies during ureteral distension demonstrate purinergic
involvement, suggesting that specific P2X3 antagonists may have
efficacy in alleviating renal colic.

Synergistic effects of ATP and oxytocin in increasing [Ca2+]i in
mouse mammary myoepithelial cells suggests that activation of
purinergic receptors may facilitate myoepithelial cell contraction in
the milk-ejection response. P2Y2 receptors on apical and basolateral
membranes appear to be involved.

Micromolar concentrations of ATP stimulate biphasic change in
transepithelial conductance in the human uterine cervix, phase 1
mediated by the P2Y2 receptor, phase II by the P2X4 receptor. Given
the potential role of ATP regulation of cervical paracellular
permeability for human fertility, contraception and health, these
findings may have clinical significance and may lead to the
development of drugs that can target specific signalling pathways in
the cervix.

FUTURE DEVELOPMENTS

Although in its infancy, the clinical manipulation of purinergic
signalling has begun. Several clinically relevant pharmacological
interventions are already part of day-to-day practice. However, one
of the main reasons why we do not yet have more purinergic
therapies in our formularies is the current sparsity of receptor-
subtype-specific agonists and antagonists that are effective in vivo.
In addition to the development of selective agonists and antagonists

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